F. M. Singer et al., "New Inhibitors of in vitro Conversion of Acetate and Mevalonate to Cholesterol", Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, "Inhibition of Hepatic Cholesterol biosynthesis by 3,5-Dihydroxy-3,4,4,-trimethylvaleric Acid and its Site of Action," Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Singer et al. reported that fluoromevalonic acid is more effective in inhibiting biosynthesis of cholesterol (as measured by in vitro conversion of labeled acetate and labeled mevalonate into cholesterol) than .DELTA.4-androstene-17.alpha.-ol-3-one-17.beta.-oic acid and .DELTA.1-testololactone.
Hulcher reported that an analog of mevalonic acid, namely, 3,5-dihydroxy-3,4,4-trimethylvaleric acid strongly inhibits cholesterol biosynthesis by rat liver homogenates.
U.S. Pat. No. 3,983,140 to Endo et al. discloses the fermentation product ML-236B referred to generically as compactin ##STR3## (also referred to as mevastatin) which is prepared by cultivation of a microorganism of the genus Penicillium. This fermentation process is disclosed in U.S. Pat. No. 4,049,495 issued Sept. 20, 1977 to Endo et al.
Brown, A. G., et al., (Beecham Pharmaceuticals Research Div.), "Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite from Penicillium Brevicompactum", J. Chem. Soc. Perkin I. 1165-1170 (1976) confirms that compactin has a complex mevalonolactone structure as disclosed by Endo et al. in the above patents.
U.S. Pat. No. 4,231,938 to Monaghan et al. discloses mevinolin (lovastatin, Monacolin K) ##STR4## (also referred to as MK-803) which is prepared by culturing a microorganism of the genus Aspergillus.
U.S. Pat. No. 4,346,227 to Terahara et al discloses pravastatin ##STR5##
Pravastatin is prepared by the enzymatic hydroxylation of compactin or its carboxylic acid as disclosed in U.S. Pat. No. 4,410,629 to Terahara et al.
U.S. Pat. No. 4,448,979 issued May 15, 1984 to Terahara et al discloses the lactone of pravastatin.
U.S. Pat. Nos. 4,444,784 and 4,450,171 to Hoffman et al disclose various antihypercholesterolemic compounds including synvinolin (simvastatin) ##STR6## as well as compounds of the structures ##STR7## wherein R.sup.1 is H or CH.sub.3, R can be an alkyl group including ##STR8## X, Y and Z are single and/or double bonds in all possible combinations.
European Patent Application 0065835A1 filed by Sankyo discloses cholesterol biosynthesis inhibiting compounds of the structure ##STR9## and their corresponding free carboyxlic acids, which may be represented by the following formula ##STR10## (in which one of R.sup.1 and R.sup.2 represents a hydrogen atom and the other represents a hydroxy group), and salts and esters of the carboxylic acids.
European Patent Application 0142146A2 filed by Merck discloses mevinolin-like compounds of the structure ##STR11## wherein R.sup.1 is
(1) hydrogen, PA1 (2) C.sub.1-4 alkyl, PA1 (3) 2,3-dihydroxypropyl, PA1 (4) alkali metal cation, such as Na.sup.+, or K.sup.+, or PA1 (5) ammonium of formula N.sup.+ R.sup.3 R.sup.4 R.sup.5 R.sup.6 wherein R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-4 alkyl or two of R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are joined together to form a 5 or 6-membered heterocycle such as pyrrolidino or piperidino with the nitrogen to which they are attached; PA1 X is --O-- or &gt;NR.sup.9 wherein PA1 R.sup.9 is H or C.sub.1-3 alkyl; PA1 R.sup.7 is C.sub.2-8 alkyl; and PA1 R.sup.8 is H or --CH.sub.3 ; ##STR13## wherein R.sup.10, R.sup.11 and R.sup.12 are independently (a) hydrogen, PA1 (b) halogen, such as bromo, chloro or fluoro, PA1 (c) C.sub.1-4 alkyl, PA1 (d) halo-C.sub.1-4 alkyl, PA1 (e) phenyl either unsubstituted or substituted with one or more of PA1 (f) OR.sup.13 wherein R.sup.13 is PA1 (1) methyl, PA1 (2) hydroxy, PA1 (3) C.sub.1-4 alkoxy, PA1 (4) oxo or PA1 (5) halo.
E is --CH.sub.2 CH.sub.2 --, --CH.dbd.CH--, or --(CH.sub.2).sub.3 --; and Z is ##STR12## wherein the dotted lines represent all of the possible oxidation states of the bicyclic system such as naphthalene, dihydro-, tetrahydro-, hexahydro-, octahydro-, and decahydronaphthalene; PA0 R.sup.15 is PA0 "But in all instances the active compound included a 4-hydroxytetrahydropyran-2-one ring or the corresponding 3,5-dihydroxy acid, or derivatives thereof, formed by opening the pyranone ring such as: ##STR16## In all of these compounds the 3,5-dihydroxy acid or corresponding lactone moiety is present and the particular stereochemistry depicted is essential for manifestation of the optimum enzyme inhibitory activity. PA0 With the present invention there are provided compounds structurally related to those lactones and dihydroxy acids that do not have the 5-hydroxy functionality, do not form a lactone ring, and are incapable of stereochemical variation at the 5-position of the acid because the 5-carbon is not asymmetric. On the contrary, the 5-carbon carries an oxo function which greatly facilitates the total synthesis of active compounds in that by eliminating one asymmetric center it is unnecessary to separate diastereoisomers or to conduct a stereoselective synthesis to obtain optimum enzyme inhibitory activity.
(i) C.sub.1-4 alkyl, PA2 (ii) C.sub.1-4 alkyl, PA2 (iii) C.sub.2-8 alkanoyloxy, or PA2 (iv) halo-C.sub.1-4 alkyl, PA2 (v) halo, such as bromo, chloro or fluoro, PA2 (i) hydrogen, PA2 (ii) C.sub.1-8 alkanoyl, PA2 (iii) benzoyl, PA2 (iv) phenyl, PA2 (v) halophenyl, PA2 (vi) phenyl-C.sub.1-3 alkyl, either unsubstituted or substituted with one or more halogen, C.sub.1-4 alkoxy, C.sub.1-4 alkyl or halo-C.sub.1-4 alkyl, PA2 (vii) C.sub.1-9 alkyl, PA2 (viii) cinnamyl, PA2 (ix) halo-C.sub.1-4 alkyl, PA2 (x) allyl, PA2 (xi) C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl, PA2 (Xii) adamantyl-C.sub.1-3 alkyl, ##STR14## wherein n is 0-2, and R.sup.14 is halo such as chloro, bromo or fluoro, or C.sub.1-4 alkyl, and ##STR15## wherein the dotted lines represent possible double bonds there being 0, 1 or 2 double bonds; m represents 1, 2 or 3; and
In the discussion of the prior art at pages 2 and 3 of the above European patent, it is indicated that HMG CoA reductase inhibitors reported in the patent literature and elsewhere include compactin; mevinolin, di- and tetrahydro derivatives thereof; analogs with different esters in the 8-position of the polyhydronaphthalene moiety, totally synthetic analogs, wherein the polyhydronaphthalene moiety is replaced by substituted mono- and bicyclic aromatics. The applicant states at pages 3 and 4 as follows:
It is believed that structures I are reduced in situ to generate the "active" inhibitors of structure II or IIa."